Liver International ISSN 1478-3223

REVIEW

Diabetes mellitus in patients with cirrhosis: clinical implications and

management

rie Paradis3,6,7 and
Laure Elkrief1, Pierre-Emmanuel Rautou2,3,4, Shiv Sarin5, Dominique Valla2,3,6, Vale
2,3,6
Richard Moreau
1 Service de Gastroent
erologie et H

epatologie, Ho^pitaux Universitaires de Geneve, Geneve, Suisse
2 DHU UNITY, Service d’H
^pital Beaujon, APHP, Clichy, France
epatologie, Ho
3 Universit

e Paris-Diderot, Sorbonne Paris Cit

e, Paris, France
4 Inserm U970, Paris Research Cardiovascular Center, Paris, France
5 Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
6 Inserm U1149, Centre de Recherche sur l’Inflammation CRI, Clichy, France
7 DHU UNITY, Pathology Department, Ho ^pital Beaujon, APHP, Clichy, France

Liver Int. 2016; 36: 936–948. DOI: 10.1111/liv.13115

Abstract
Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver
diseases. In patients with cirrhosis, diabetes can be either a classical type 2 diabetes mellitus or the so-called hepatoge-
nous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview
of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with
portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contribut-
ing to peripheral insulin resistance through insulin receptors down-regulation. Moreover, cirrhosis is associated with
increased levels of advanced-glycation-end products and hypoxia-inducible-factors, which may play a role in the devel-
opment of diabetes. This review also focuses on the clinical implications of diabetes in patients with cirrhosis. First, dia-
betes is an independent factor for poor prognosis in patients with cirrhosis. Specifically, diabetes is associated with the
occurrence of major complications of cirrhosis, including ascites and renal dysfunction, hepatic encephalopathy and
bacterial infections. Diabetes is also associated with an increased risk of hepatocellular carcinoma in patients with
chronic liver diseases. Last, the management of patients with concurrent diabetes and liver disease is also addressed.
Recent findings suggest a beneficial impact of metformin in patients with chronic liver diseases. Insulin is often
required in patients with advanced cirrhosis. However, the favourable impact of controlling diabetes in patients with
cirrhosis has not been demonstrated yet.

Keywords
ascites – hepatic encephalopathy – hepatocellular carcinoma – hepatogenous diabetes – metformin

Abbreviations
AGEs, advanced glycation-end products; CTGF, connective tissue growth factor; DPP-4, Dipeptyl peptidase-4; GLP-1, glucagon-like peptide-1;
HbA1c, glycated haemoglobin; HCC, hepatocellular carcinoma; HIF, hypoxia inducible factor; IGF1, insulin growth factor-1; MELD, model for end-
stage liver disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor.
Correspondence
Dr Laure Elkrief, Service de Gastroent

erologie et H
epatologie, Avenue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland.
Tel: +41 79 55 33 704; Fax: +41 22 37 29366
e-mail: Laure.elkrief@hcuge.ch
The Institute of Liver and Biliary Sciences has been endorsed by the Inserm as an International Laboratory associated to the INSERM Unit 1149 and
Universit

e Paris-Diderot, Sorbonne Paris Cit
e, Paris, both in France.
Handling Editor: Isabelle Leclercq
Received 22 June 2015; Accepted 7 March 2016
Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1111/liv.13115/suppinfo

Liver International (2016)

936 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Elkrief et al.
Key points
• In patients with cirrhosis, diabetes may be either a
consequence of liver disease or an underlying type 2
diabetes
• In patients with cirrhosis, fasting blood glucose
may be normal despite diabetes. Oral glucose toler-
ance test allows diagnosing diabetes.
• Diabetes is a factor of poor survival and increases
the risk of complications of cirrhosis. This suggests
that active screening and management of diabetes
could be beneficial in patients with cirrhosis.
• The use of metformin seems safe and may have a
beneficial impact on patients’ outcome. However, no
treatment has been proven to improve the prognosis
of patients with cirrhosis and concurrent diabetes.
The liver plays a pivotal role in glucose homeostasis. It
stores glycogen in the fed state and produces glucose
through glycogenolysis and gluconeogenesis in the fasting
state. There are close relationships between liver diseases
and disorders of glucose metabolism. On the one hand,
the risk of death from chronic liver diseases is increased in
patients with type 2 diabetes mellitus (1–3). One the other
hand, the presence of diabetes in patients with cirrhosis is
an independent factor for poor survival, and is associated
with the major complications of cirrhosis. The treatment
of diabetes in patients with chronic liver diseases is com-
plex, because of impaired liver and/or renal functions, and
of the potential hepatotoxicity of oral hypoglycaemic
agents. The aim of this review is to provide an update on
the relationships between cirrhosis and diabetes. We will
focus on recent advances in the pathophysiological mech-
anisms, diagnosis, clinical implications and therapeutic
management of diabetes in patients with cirrhosis.
Impact of diabetes on progression of liver fibrosis
and cirrhosis development
Epidemiological links between type 2 diabetes and
cirrhosis
Type 2 diabetes is a risk factor for liver fibrosis develop-
ment and progression. There is a strong relationship
between the components of the insulin resistance syn-
drome and the stage of liver fibrosis (4, 5). Several inde-
pendent groups observed in large cohorts of patients
that type 2 diabetes is associated with a 2 to 2.5-fold
increased risk of cirrhosis development, and of death
from chronic liver diseases, mainly attributable to non-
alcoholic fatty liver diseases (NAFLD) (1–3). Interest-
ingly, the effect of diabetes on fibrosis has been found to
be independent from other components of the meta-
bolic syndrome (6). Furthermore, recent cohort studies
in Taiwan showed that diabetes mellitus is an indepen-
dent predictor of cirrhosis in patients with chronic hep-
atitis B and chronic hepatitis C (7, 8).
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Diabetes mellitus in cirrhosis
Pathophysiological mechanisms promoting liver fibrosis
in patients with insulin resistance or type 2 diabetes
As a part of metabolic syndrome, type 2 diabetes can
promote NAFLD. Patients with isolated steatosis gener-
ally have an excellent prognosis, while patients with
non-alcoholic steatohepatitis (NASH) may develop
fibrosis leading to cirrhosis and its complications (6).
Pathophysiological mechanisms leading to NASH and
NASH-related fibrosis have been recently reviewed in
detail elsewhere (9). Moreover, diabetes likely con-
tributes to fibrosis progression and cirrhosis indepen-
dently from NAFLD by modulating several key
processes implicated in fibrogenesis, which are detailed
below.
Activation of hepatic stellate cells
Hepatic stellate cells, the liver-specific pericytes, are
localized in the space of Disse. In a chronically injured
liver, hepatic stellate cells promote liver fibrosis through
excessive extra-cellular matrix production and reduced
extra-cellular matrix degradation (10). Glucose and
insulin have profibrogenic properties on hepatic stellate
cells. Indeed, incubation of hepatic stellate cells with
high glucose or insulin levels leads to overexpression of
the key profibrogenic gene connective tissue growth fac-
tor (CTGF) (11). Hyperglycaemia and oxidative stress
contribute to the accumulation of advanced-glycation-
end (AGE) products. Interestingly, functional receptors
for AGE products are overexpressed in activated hepatic
stellate cells (12). This up-regulation of receptors for
AGE products suggests that insulin and hyperglycaemia
may also activate hepatic stellate cells through the liga-
tion of AGE products on their receptors.
Inflammation
Inflammation is a major player in the development of
liver fibrosis. (13). The link between diabetes and
inflammation is now well established and type 2 dia-
betes is viewed as an auto-inflammatory disease (14).
Inflammation plays a crucial role in the pathogenesis of
diabetes-related complications. For instance, inflamma-
tion and subsequent extracellular matrix expansion play
a key role in the development and progression of dia-
betic nephropathy (15). Regarding the liver, indirect
data suggest that systemic inflammation associated with
insulin-resistance and diabetes might contribute to pro-
gression of liver fibrosis. In patients with hepatitis C,
insulin resistance and diabetes are associated with liver
fibrosis progression as well as with necroinflammatory
activity (16, 17).
Apoptosis
Apoptosis is a type of cell death characterized by the
fragmentation of the dying cell into membrane-bound
937
Diabetes mellitus in cirrhosis
vesicles, called apoptotic bodies. Apoptosis is a key
player in the progression of liver fibrosis (18). Engulf-
ment of apoptotic bodies by hepatic stellate cells
stimulates their fibrogenic activity and may be one
mechanism by which hepatocyte apoptosis promotes
fibrosis (19). Indirect data suggest that diabetes might
promote fiborsis through aptoptosis. First, the dysreg-
ulation of the insulin receptor pathway, associated
with insulin resistance, promotes liver cell apoptosis
(20). In patients with NASH, plasma cytokeratin 18
substrates, a biomarker of liver apoptosis, is associ-
ated with liver fibrosis (21, 22). However, the associa-
tion between diabetes and apoptosis remains to be
evaluated.
Angiogenesis
Angiogenesis consists in the formation of new vascular
structures from pre-existing blood vessels. Excessive
angiogenesis plays a major role in the pathophysiology
of diabetic complications including nephropathy,
retinopathy as well as macrovascular diseases (23).
Interestingly, excessive angiogenesis plays a role in the
pathophysiology of these diseases and promotes fibrosis
through the activation of CTGF (24–26).
Pathological angiogenesis has also been described in
chronic liver diseases, including NASH (27). First, it has
been shown that leptin-mediated neovascularisation,
coordinated by vascular endothelial growth factor
(VEGF), plays an important role in the development of
liver fibrosis in a rat model of NASH (28). More
recently, the same group showed that CD34 expression,
a marker of neovascularisation, was overexpressed in
the liver of patients with NASH. Furthermore, there was
Fig. 1. Proposed pathophysiology of diabetes mellitus in patients with cirrhosis.
938
Elkrief et al.
a positive correlation between neovascularisation and
insulin resistance as well as with liver fibrosis (29). Thus,
this suggests that insulin resistance and diabetes, as in
other tissues, promote liver fibrosis through angiogene-
sis. Yet, the impact of diabetes, outside the context of
NASH, on excessive angiogenesis and subsequent liver
fibrosis has not been evaluated.
Hepatic sinusoidal capillarization
Hepatic sinusoidal capillarization refers to the loss of
endothelial cell fenestration, associated with the depo-
sition of collagen and other extracellular matrix pro-
teins in the space of Disse. This mechanism is
implicated in the progression of liver fibrosis (30).
The role of insulin signalling and of hyperglycaemia
on sinusoidal endothelial cells and their impact on
liver fibrogenesis has not been studied (31). Yet, the
increase in extra-cellular matrix deposition in the
space of Disse typically observed in liver biopsies from
patients with diabetes suggests that hepatic sinusoidal
capillarization may promote liver fibrosis in the dia-
betes setting (32–34).
Impact of cirrhosis on glucose homeostasis
In a normal individual, the liver plays a key role in
maintaining glucose homeostasis. In patients with
advanced cirrhosis, alterations in glucose metabolism,
the so-called hepatogenous diabetes, have been
described. Fig. 1 summarizes the potential mecha-
nisms which might participate into the occurrence of
hepatogenous diabetes mellitus in patients with cir-
rhosis.
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Elkrief et al.
Decreased insulin clearance by the liver
In patients with cirrhosis, several structural changes
can decrease the extraction of insulin by the liver,
leading to increased systemic insulin levels. These
structural modifications include: (a) a reduction in
liver cell mass, which decreases the clearance of insulin
(35) because insulin is metabolized and degraded
mainly by parenchymal liver cells (36); (b) portosys-
temic venous collaterals, because of the decreased hep-
atic first-pass extraction, resulting in high levels of
insulin. In patients with cirrhosis and surgical porto-
caval shunts, insulin levels in the hepatic veins are
markedly increased, compared to patients without sur-
gical shunts. By contrast, C-peptide levels do not dif-
fer between patients with cirrhosis and controls (37).
This view is also supported by the fact that glucose
control deteriorates and circulating insulin levels
increase after transjugular intrahepatic portosystemic
shunt placement in diabetic patients (38).
Subsequently, hyperinsulinaemia can lead to resis-
tance to insulin through insulin receptor down-regula-
tion. Indeed, hyperinsulinaemia induces a reduction in
insulin receptor affinity, a reduction in the number of
receptors exposed at the surface of the target cell and a
diminution of the effectiveness of the insulin receptor as
a transmitter of stimulatory signals (39).
Increased advanced-glycation-end products
Although hyperglycaemia fosters the AGEs, AGEs could
also induce insulin resistance and beta-cell injury prior
to diabetes onset (40). Besides the kidney, the liver also
seems to be involved in the removal of AGEs (41). In
patients with cirrhosis without diabetes, plasma AGE
levels are markedly elevated and correlate with the
severity of the liver disease (42, 43). After liver trans-
plantation, a clear decline in AGEs levels occurs (42).
According to these findings, it can be speculated that in
patients with cirrhosis, the accumulation of AGEs,
related to a reduced removal of AGEs, may promote
diabetes.
Hypoxia and hypoxia-inducible factors
Systemic hypoxia is observed in patients with advanced
cirrhosis, and is related to the severity of the liver disease
(44). The hypoxia-inducible factors (HIFs) are a family
of transcriptional regulators that induce a homeostatic
response to hypoxia in virtually all cells and tissues.
HIFs have been implicated in the development of liver
fibrosis in in vitro and murine models (45, 46). HIFs
also play a key role in glucose metabolism, and are
implicated in the development of diabetes mellitus (47).
HIF, namely HIF-1a, is also important for pancreatic b-
cell reserve. However, the mechanisms are complex.
Indeed, in HIF-1 knock-out mice, pancreatic b-cell
function is impaired (48). Mild increase in HIF-1a is
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Diabetes mellitus in cirrhosis
beneficial for b-cell function and glucose tolerance. By
contrast, very high levels of HIF-1, such as those observe
in severe hypoxia are clearly deleterious for b-cell func-
tion (48). Thus, cirrhosis-related hypoxia might be
hypothetized to promote the occurrence of hepatoge-
nous diabetes mellitus.
A liver–pancreas axis
Glucose intolerance in cirrhosis results from peripheral
insulin resistance and hyperinsulinaemia. Interestingly,
in patients with cirrhosis and overt diabetes, beta-cell
secretion, in response to hyperglycaemia is significantly
reduced, compared to patients with cirrhosis and nor-
mal glucose tolerance as well as those with glucose intol-
erance (49), suggesting that an altered secretion of
insulin by beta cells may contribute to the development
of overt diabetes (36). Recently, Yi and colleagues
observed that a hormone named betatrophin, primarily
expressed in the hepatocytes, induced b-cell prolifera-
tion and improved glucose tolerance in a murine model
(50). However, recent data suggest that betatrophin
levels might rather be associated with insulin resistance,
rather than b-cell proliferation. Betatrophin levels were
found to be increased in patients with type 2 diabetes
compared to non-diabetic subjects (51–54). Further-
more, in a recent study including more than 1000 non-
diabetic subjects, there was a strong correlation between
betatrophin levels and HOMA-IR (54). Plasma betat-
rophin levels were significantly increased in patients
with cirrhosis compared to healthy individuals. Betat-
rophin levels were also associated with liver disease
severity. Moreover, betatrophin levels were significantly
higher in patients with insulin resistance than in those
without (55). These findings support a possible func-
tional role of betatrophin in type 2 diabetes, where it
could play a role in compensating for the increased
insulin demand despite liver insufficiency.
Diagnosis and clinical presentation of diabetes in
patients with cirrhosis
In patients with cirrhosis, disorders of glucose metabo-
lism range from mere glucose intolerance to overt dia-
betes. It is estimated that only 30% of the patients have
normal glucose tolerance, 30–50% have impaired glu-
cose tolerance and up to 30% have overt diabetes (56–
59). This is much higher than in the general population,
where the prevalence of glucose intolerance is around
15% and that of diabetes is 8% (60, 61).
The diagnosis of diabetes in patients with cirrhosis
may not be easy. First, at early stage, fasting serum
glucose levels is normal in 23% of the patients with
overt diabetes (57). Indeed, such patients have nor-
mal fasting blood glucose, whereas post-prandial
blood glucose is >200 mg/L (62). Thus, an oral glu-
cose tolerance test is needed to detect the impairment
of glucose metabolism.
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Diabetes mellitus in cirrhosis Elkrief et al.

Furthermore, discrimination between type 2 diabetes
and hepatogenous diabetes is frequently not possible.
Still, hepatogenous diabetes may have different clinical
characteristics from type 2 diabetes. Among 50 patients
with hepatogenous diabetes, only 16% of patients had a
family history of diabetes. Only 8% had retinopathy.
After a mean follow-up of 5 years, no cardiovascular
deaths was reported, whereas 52% of the patients had
died, mainly from complications of cirrhosis (56). This
may be either related to the shorter duration of diabetes
in patients with hepatogenous diabetes than in patients
with type 2 diabetes or to the fact that mortality is
mostly related to cirrhosis-related complications in
these patients (63).
In patients with isolated hepatogenous diabetes, liver
transplantation by itself can normalize glucose tolerance
and insulin sensitivity (64), supporting the idea that dia-
betes was related to cirrhosis. However, post-transplan-
tation diabetes remains a very common condition, as it
is estimated that about 30% of liver transplant recipients
have diabetes (65). Interestingly, in patients receiving a
liver graft, pretransplantation diabetes, as well as
advanced age, family history of diabetes, and maximum
body mass index over 25 kg/m2 (which are risk factors
for type 2 diabetes), is associated with the development
of post-transplantation diabetes (66). These data suggest
that diabetes mellitus present at the time of liver trans-
plantation was not only exclusively related to advanced
liver disease but also to pre-existing metabolic abnor-
malities. The causes of liver disease also appear to be an
important risk factor for the development of diabetes in
patients with cirrhosis. Indeed, diabetes is more fre-
quent in patients with hepatitis C-related cirrhosis (67,
68) or alcohol-related cirrhosis than in patients with bil-
iary cirrhosis (69). However, cirrhosis remains indepen-
dently associated with cirrhosis. Indeed, among patients
with hepatitis C infection, diabetes is more frequently
observed in patients with cirrhosis (24%) than in those
without (6%) (70).
Measurement of glycated haemoglobin (HbA1c) does
not accurately reflect glycaemic status in patients with
cirrhosis. In patients without liver diseases, HbA1c is
used for routine evaluation and the management of
patients with diabetes. HbA1c concentration reflects the
previous 2–3 months of glycaemic status and is well
correlated with the development of diabetes-related
complications (71, 72). Studies on small-sized series of
patients indicate that HbA1c measurement is not accu-
rate in patients with cirrhosis (73–75). Indeed, 40% of
the non-diabetic patients with cirrhosis had HbA1c val-
ues below the normal range in a non-diabetic reference
population (75, 76). Furthermore, patients with cirrho-
sis and concurrent diabetes also had HbA1c values in
the non-diabetic reference, namely between 4 and 6%
(76). Only a small proportion of patients with cirrhosis
and diabetes had high HbA1c (76). Furthermore,
patients with cirrhosis showed similar values of HbA1c
compared to control patients, although fasting plasma
glucose was higher in patients with cirrhosis (74). The
reason why HbA1c measurement is not accurately
reflecting glycaemic control in patients with cirrhosis
remains unclear. Shortened erythrocyte life span, which
is common in patients with cirrhosis and is known to
cause low HbA1c values, could play a role independent
of glycaemia. Fructosamine measurement reflects gly-
caemic status over a period of 2–4 weeks. Fructosamine
level appears to be a more accurate tool than HbA1c for
monitoring glycaemic control in patients with cirrhosis
(75, 76) .
Prognostic impact of diabetes in patients with
cirrhosis
Survival
The prognostic value of diabetes in cirrhosis has previ-
ously been investigated only in a limited number of
studies on selected patients. Some studies included
patients with advanced cirrhosis, whereas others
included patients with well-compensated cirrhosis; most
of these studies found that diabetes was associated with
a lower survival (57–59, 63, 77–79) (Table 1). Recently,
a French cohort study of 348 patients with hepatitis C-
related cirrhosis admitted to hospital found that dia-
betes was associated with a shorter transplantation-free
survival, independent of model for end-stage liver dis-
ease (MELD) score (Odds ratio 1.3). Diabetes markedly
influenced the prognosis in patients with baseline
MELD score <10. By contrast, diabetes had no impact
on survival in patients with a baseline MELD score ≥10
(63). These findings suggest that the severity of liver dis-
ease masks the deleterious effect of diabetes and/or that

Table 1. Studies evaluating the prognostic impact of diabetes in patients with cirrhosis
Author (ref) Year Patients Type of study Characteristics of the patients Follow-up Survival (diabetics vs. non diabetic)
Bianchi (77) 1984 382 Retrospective Hospitalized 37 months 64 vs. 82% (P = 0.005)
Moreau (78) 2004 100 Prospective Refractory ascites 2 years 18 vs. 58% (P = 0.0004)
Nishida (76) 2006 56 Prospective Various aetiologies 5 years 56 vs. 95% (P < 0.05)
Sangiovanni (98) 2006 214 Retrospective HCV compensated cirrhosis 17 years No difference
Berman (96) 2011 447 Retrospective Hospitalized 90 days No difference
Quintana (97) 2011 110 Prospective Compensated cirrhosis 2.5 years 69 vs. 48% (P < 0.05)
Elkrief (82) 2014 348 Retrospective Hospitalized HCV cirrhosis 4.5 years 24 vs. 34% (P = 0.03)

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Elkrief et al.
in patients with high MELD score, diabetes related to
cirrhosis, and thus has no independent effect on sur-
vival.
Hepatocellular carcinoma
It is now well established that the risk of cancer is
increased in patients with type 2 diabetes, including
hepatocellular carcinoma (HCC) (80). In a meta-analy-
sis of 28 prospective studies, pre-existing diabetes was
significantly associated with an increased incidence of
HCC (relative risk 1.87) and HCC-specific mortality
(relative risk 1.88) (81). Yet, no practical recommenda-
tions can be suggested for patients with cirrhosis and
diabetes. In patients with cirrhosis, compared to
patients undergoing ultrasound surveillance every
6 months, three-month ultrasonographical examination
did not improve either the rate of detection of small
HCCs eligible for curative treatment or the overall sur-
vival rate compared to patients undergoing surveillance
every 6 months (82).
Ascites and renal dysfunction
We recently reported that diabetes is associated with the
development of ascites, independent of MELD score in
patients with hepatitis C-related cirrhosis (63). Diabetes
also seems to be associated with refractory ascites.
Indeed, in a French prospective study of 100 patients
with cirrhosis and refractory ascites, diabetes was more
frequently observed in patients with Child Pugh class B
than Child Pugh class C cirrhosis suggesting a role of
diabetes independent from impaired liver function (59).
These observations suggest a specific role of diabetes in
the development of ascites. However, the involved
mechanisms remain elusive. In patients with cirrhosis,
ascites formation has been related to circulatory distur-
bances, renal dysfunction and sodium retention (83).
Moreover, in patients with cirrhosis on the waiting list
for liver transplantation, diabetic nephropathy is fre-
quently observed when kidney biopsy is performed, and
is predictive of the development of renal dysfunction
after liver transplantation (84). In humans or animal
(A) (B)
Fig. 2. Pathological lesions found in the liver of patients with diabetes. Haematoxylin–eosin staining: (A) Non-alcoholic steatohepatitis fea-
tures include macrovesicular steatosis (star), hepatocyte ballooning (black arrow) and lobular inflammation (cross), (B) Metabolic cirrhosis: at
the stage of cirrhosis, typical features of NAFLD may be lacking; Picrosirius coloration: (C) perisinusoidal fibrosis (star).
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Diabetes mellitus in cirrhosis
models without cirrhosis, diabetes is associated with
specific changes in the hepatic microcirculation, called
‘hepatic microangiopathy’ (or diabetic hepatosclerosis),
characterized by non-zonal perisinusoidal deposition of
collagen and basement membrane (33, 34, 85, 86)
(Fig. 2). In patients with cirrhosis and concurrent dia-
betes, such lesions might participate into the formation
of ascites. It is thus tempting to speculate that diabetes-
associated microcirculatory changes in the liver and the
kidneys could promote ascites and renal dysfunction
(33). Supplemental Fig. S1 summarizes the mechanisms
promoting ascites in patients with cirrhosis and
diabetes.
Hepatic encephalopathy
The association between diabetes and hepatic
encephalopathy has been shown in several studies. In
the first study, among 65 patients with hepatitis C-
related cirrhosis, severe hepatic encephalopathy was
more common, contrasting with a preserved liver
function (87). In the second study, in 128 patients
with cirrhosis, diabetes was associated with minimal
hepatic encephalopathy (88). Furthermore, in a recent
French cohort of 348 patients with hepatitis C-related
cirrhosis, diabetes was associated with the presence of
hepatic encephalopathy, independent of MELD score
(63). The latter study included hospitalized patients,
and only overt hepatic encephalopathy was taken into
account.
Several mechanisms by which diabetes could theoret-
ically promote hepatic encephalopathy have been inves-
tigated. First, diabetes could increase ammonia
production by enhancing small intestine glutaminase
type K. Indeed, metformin which reduces glutaminase
activity in vitro has been shown to decrease the inci-
dence of hepatic encephalopathy in patients with cirrho-
sis (89). Moreover, in a randomized control trial
including more than 100 patients, the administration of
an oral antidiabetic agent, acarbose, in patients with cir-
rhosis and concurrent diabetes significantly reduced
ammonia blood levels, and improved psychometric tests
for minimal hepatic encephalopathy (90). Second, the
(C)
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Diabetes mellitus in cirrhosis Elkrief et al.

inflammatory state associated with insulin resistance
and type 2 diabetes (91) could act synergistically with
cirrhosis and endotoxemia associated with encephalopa-
thy (92). Third, intestine motility impairment has been
described in diabetic patients as a part of autonomic
neuropathy (93). It could promote small intestine bacte-
rial overgrowth raising bacterial translocation, known to
favour hepatic encephalopathy (94).
Bacterial infections
Diabetes mellitus and cirrhosis are two conditions that
predispose to bacterial infections. Diabetes has been
associated with increased rates of bacterial infections
(95). This feature may be partially explained by a
decreased T-cell-mediated immune response (96).
Impaired neutrophil function has also been documented
in diabetic patients (97). Bacterial infections are also
more common in patients with cirrhosis than in the
general population (98). They are also more severe since
mortality is four-fold higher in infected patients with
cirrhosis than in those without (99). The mechanisms of
increased susceptibility to infections in cirrhosis are
unclear. Functional alterations of monocytes and neu-
trophils have been observed. A role for deficiencies in
C3 and C4 has also been suggested (100). The synergy of
diabetes and cirrhosis to promote infections is sup-
ported by clinical evidence. In one cohort of 178 cir-
rhotic hospitalized patients (25% had diabetes), the
prevalence of bacterial infections was more frequent in
diabetic patients than in non-diabetic (85 vs. 48%,
P < 0.0001) (101). In our cohort of 348 hospitalized
patients with HCV-related cirrhosis, diabetes was inde-
pendently associated with bacterial infections develop-
ment (63). Finally, in patients undergoing liver
transplantation, those with diabetes are at higher risk
for bacterial infections (102).
Management of diabetes in patients with cirrhosis
In patients with type 1 and type 2 diabetes, the Diabetes
Control and Complications Trial (DCCT) and the Uni-
ted Kingdom Prospective Diabetes Study (UKPDS)
studies have demonstrated that poor glycaemic control
(based on an HbA1c level above 7% for type 1 diabetes
and 6.5% for type 2 diabetes) was directly associated
with the development of diabetic micro- and macro-
angiopathy (71, 72). In patients with cirrhosis and dia-
betes, the risk of cirrhosis complications seems to be
higher than the risk of diabetes complications. The
impact of early diagnosis and treatment of diabetes on
the clinical course of patients with cirrhosis and diabetes
is unknown. However, it is tempting to speculate that it
could be beneficial. As detailed below, recent data sug-
gesting that metformin decreases the risk of HCC as well
as the risk of hepatic encephalopathy are in favour of
screening and treating diabetes in patients with cirrho-
sis.
There is no clinical trial that specifically targeted
patients with coexistent diabetes and cirrhosis. The ther-

Table 2. Therapeutics options for treatment of diabetes mellitus in patients with cirrhosis
Useful in Useful in patients
Therapy Mechanism of action type 2 DM with cirrhosis and DM Side-effects/risks
Lifestyle interventions Decrease liver and adipose fat Very useful Potentially useful Malnutrition frequent in patients
Low fat diet Increase insulin sensitivity with cirrhosis
Physical exercise Physical exercise may not be
feasible in patients with
advanced cirrhosis
(edema, ascites)
Metformin Increase insulin sensitivity Very useful Very useful Contraindicated in patients with
renal dysfunction
Theoretical risk of lactic acidosis
Thiazolidinediones Increase insulin sensitivity Useful No available data Reported hepatotoxicity
Usefulness in patients with
NASH has not been
demonstrated
Secretagogues Increase endogenous Useful Not useful Contraindicated in patients
Sulphonyureas production of insulin with advanced cirrhosis
Glinides because of the risk of
hypoglycaemia
Incretins Increase insulin sensitiviy Very useful No available data
GLP-1 receptor analogues Obese patients
DPP-4 inhibitors (weight loss)
Alpha-glucosidase inhibitors Decrease carbohydrate Useful May be useful in Benign digestive side-effects
absorption in the bowel patients with HE
Insulin Substitutive treatment Often necessary Often necessary Risk of hypoglycaemia

DM, diabetes mellitus; NASH, non-alcoholic steatohepatitis; GLP-1, glucagon-like peptide-1; DPP-4, dipeptyl peptidase-4; HE, hepatic encephalopathy.

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942 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Elkrief et al.
apeutic options for diabetes, and their potential benefit
in patients with cirrhosis, are summarized in Table 2.
An algorithm for the management of diabetes in
patients with cirrhosis is proposed in Fig. 3.
Lifestyle interventions
The first-line therapy for type 2 diabetes consists of life-
style changes, which includes hypocaloric diet and physical
exercise. The goal of physical exercise is to increase periph-
eral insulin sensitivity. Unfortunately, in patients with cir-
rhosis, such therapies may be inappropriate or unfeasible.
Indeed, up to 50 percent of cirrhotic patients have malnu-
trition (103), a contraindication to hypocaloric diet. Fur-
thermore, ascites and edema hamper physical exercise.
Pharmacologic therapies
Pharmacologic options for the control of diabetes in
patients with liver diseases are, for the most part, similar
to patients without liver disease. Only patients with sev-
ere impaired liver function have altered drug metabo-
lism. Regarding the risk of hepatotoxicity, while patients
with liver disease are not predisposed to hepatotoxicity,
the underlying liver disease may increase the severity of
drug-induced liver injury (104).
Metformin
First-line therapy with metformin is theoretically appro-
priate in patients with cirrhosis because it decreases
insulin resistance. Metformin has long been considered
to be contraindicated in patients with advanced liver
disease because of a theoretical increase in the risk of
Universal screening
Fasting plasma glucose
If normal: oral glucose tolerance test
Overt diabetes
Step 1 : lifestyle intervention*
Poor glucose control after 3 months
Step 2: medical treatment
Normal renal fonction Impaired renal fonction**
Metformin
Insulin
Poor glucose control
after 3 months
Fig. 3. Proposed algorithm for the management of diabetes mellitus in patients with cirrhosis.
Liver International (2016)
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Diabetes mellitus in cirrhosis
lactic acidosis (105). Yet, despite the widespread use of
metformin, only rare patients with cirrhosis developed
lactic acidosis, suggesting that metformin is safe in
patients with cirrhosis without renal dysfunction (106–
109) (Supplemental Table S1).
A growing number of observational studies suggest
that metformin (relative to other glucose-lowering ther-
apies) could be associated with a reduced risk of cancer
or cancer mortality, including hepatocellular carcinoma
(110, 111). Furthermore, Zhang et al. recently reported
that continuation of metformin in patients with newly
diagnosed cirrhosis is associated with a longer survival
(112). In a recent cohort of 82 patients with cirrhosis
and diabetes, the occurrence of hepatic encephalopathy
was significantly lower in patients receiving metformin
(5 vs. 41%) (89). An indication bias may limit the inter-
pretation of observational studies, as metformin is most
typically prescribed to patients with short duration of
diabetes and without contraindicating factors (advanced
age, liver or kidney disease) that also might impact the
prognosis (113). However, these data suggest that
metformin is the first-choice therapy for patients with
cirrhosis and diabetes.
Thiazolidindiones
Thiazolidinediones are insulin-sensitizing peroxisome
proliferator-activated receptor (PPAR) gamma ago-
nists that do not increase insulin secretion directly or
cause hypoglycaemia when used alone. Thus, thiazo-
lidinediones may be particularly useful in patients
with diabetes and chronic liver diseases. However,
troglitazone and rosiglitazone have been withdrawn
from the market because of their potential hepato-
No diabetes
Repeat screening every
2 years
* Control weight, increase physical activity
** Filtration glomerular rate <50 ml/min
943
Diabetes mellitus in cirrhosis
toxic effect and the risk of congestive heart failure
respectively. Pioglitazone is still currently available. In
patients with NASH, the usefulness of thiazolidine-
diones is debated (114). A meta-analysis of four ran-
domized controlled trials found that
thiazolidinediones significantly improve steatosis and
liver inflammation, but not fibrosis (115). Patients
with cirrhosis were excluded from these trials.
Insulin secretagogues
Insulin secretagogues include sulphonylureas and glin-
ides. They trigger insulin release by the pancreatic beta
cells. Thus, in patients with cirrhosis, they may not be
the first-choice option, as they do not modify insulin
sensitivity. Moreover, patients with cirrhosis, especially
those with alcohol-related cirrhosis, may have pancre-
atic beta-islets cell damage. Most importantly, there is
an increased risk of hypoglycaemia with these therapies.
Thus, secretagogues are not recommended in patients
with high risk of hypoglycaemia (105).
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors (acarbose) could be useful
in patients with cirrhosis, since they reduce carbohy-
drate absorption in the bowel, which would decrease the
risk of postprandial hyperglycaemia. Indeed, patients
with cirrhosis and diabetes frequently have normal
plasma fasting glucose and abnormal oral glucose toler-
ance test (56, 57). In a randomized, double-blind study
including 100 patients with compensated cirrhosis and
insulin-treated diabetes, the control of postprandial and
fasting blood glucose levels improved significantly with
the use of acarbose (116). In another crossover placebo-
controlled study involving patients with hepatic
encephalopathy, there was a significant improvement in
postprandial blood glucose level in patients treated with
acarbose (90).
Dipeptyl peptidase-4 inhibitors and glucagon-like peptide-
1 receptor agonists
Glucagon-like peptide-1 is a gut-derived incretin hor-
mone that stimulates insulin and suppresses glucagon
secretion, inhibits gastric emptying and reduces appetite
and food intake. Therapeutic approaches for enhancing
incretin action include DDP-4 inhibitors and GLP-1
analogues. These classes of therapeutic agents for type 2
diabetes were developed in the past 10 years and have
proven to be effective glucose lowering agents. In addi-
tion, GLP-1 analogues promote (moderate) weight loss
(117). So far, preclinical studies have found that incre-
tins can improve hepatic steatosis (118). Although some
effects could be because of an overall improvement in
metabolic parameters, there are data to support
improvements independent from weight loss, as well as
direct effect on the hepatocyte. However, the safety and
944
Elkrief et al.
the usefulness of incretins in patients with cirrhosis need
further investigations.
Insulin
Despite the potential interest of oral antidiabetic agents,
insulin therapy is frequently prescribed in patients with
cirrhosis, especially in those with advanced cirrhosis.
Among 348 patients with hepatitis C-related cirrhosis,
62% were on insulin therapy 63).
Importantly, caution must be made regarding the
dosage of insulin therapy. Indeed, insulin requirements
in patients with cirrhosis may vary depending on the
severity of cirrhosis. In patients with compensated cir-
rhosis, insulin requirement may be important because
insulin resistance predominates. In patients with decom-
pensated cirrhosis, the hepatic metabolism of insulin is
reduced, which decreases the needs for insulin. There-
fore, hospitalization might be safe for the initiation of
insulin therapy, by allowing for close monitoring of
blood glucose levels, to reduce the risk of hypoglycaemia.
Non selective beta-blockers are widely used in
patients with cirrhosis for prophylaxis of variceal bleed-
ing (119). With regard to diabetic patients under insulin
treatment, beta-blockers may make hypoglycaemic epi-
sodes less symptomatic, leading to more profound alter-
ation in mental state to develop without warning
symptoms. Moreover, hypoglycaemia can be precipi-
tated by beta-adrenergic response because b2-adreno-
ceptors normally stimulate glycogenolysis and
pancreatic release of glucagon. However, a study com-
paring subjects with diabetes receiving or not beta-
blockers found that beta-blockers did not increase the
number or the severity of hypoglycaemic episodes
(120). Thus, beta-blockers are not contraindicated in
patients with cirrhosis treated with insulin.
Conclusion
Diabetes mellitus is observed in up to 30% of patients
with cirrhosis. Diabetes can be either an underlying
type 2 diabetes mellitus or the consequence of alter-
ations directly related to an impaired liver function.
Diabetes mellitus is associated with a poor prognosis
in patients with cirrhosis, mainly because of an
increased risk of cirrhosis complications. Thus, screen-
ing for diabetes mellitus should be proposed to all
patients with cirrhosis. Although it is tempting to
speculate that controlling diabetes may have a benefi-
cial effect, further controlled studies are needed to
evaluate the effect of diabetes control on the develop-
ment of complications of cirrhosis.
Acknowledgements
Financial disclosures: None.
Conflict of interest: The authors do not have any
disclosures to report.
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© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Elkrief et al.
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Liver International (2016)
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